Infection and inflammation at the maternal-fetal interface lead to preterm labor, a major source of human morbidity and mortality. The underlying mechanisms of preterm labor remain elusive. Therefore, no effective therapies exist to-date. The maternal-fetal interface is unique because fetal cells are juxtaposed to maternal immune cells. How maternal-fetal tolerance is achieved is still poorly understood. Even less is known about host-pathogen interactions in this tissue. Evidence is accumulating that the maternal-fetal interface has strong and unique innate host defenses, suggesting that specific virulence determinants might be necessary to achieve microbial colonization. The overall goal of this research application is to understand host-pathogen interactions at the maternal-fetal interface, and to identify innate host defense pathways that protect the fetus from infection. Among the pathogens that are able to infect the maternal-fetal interface is Listeria monocytogenes, a facultative intracellular bacterium; and our model organism because it is extremely amenable to experimental analysis. We developed a pregnant guinea pig model of listeriosis that replicates human disease for in vivo studies. In addition, we have developed highly relevant model systems of human placentation, to perform in vitro experiments in systems that are physiologically highly relevant. Using these models we have identified a secreted bacterial protein specifically important for infection of the maternal-fetal interface. Further, we have discovered that a unique fetal cell population in the uterus (invasive trophoblasts) is able to restrict intracellular bacterial growth. In Aims 1 and 2 we will determine the functional roles of the placenta-specific virulence determinant that we have discovered. In Aim 3, we will identify pathways that are important for host defenses in invasive trophoblasts and test whether the placenta-specific virulence determinant we have identified interferes with these pathways. These studies will expand our knowledge of the pathogenesis of placental infections and will serve as a springboard for the development of novel strategies for prevention and therapy of preterm labor.